FR2801589A1 - 2-Aryl quinoline derivatives useful for the treatment of urinary incontinence. venous ulcers, migraine or gastro-intestinal disorders - Google Patents

Abstract

2-Aryl quinoline derivatives (I), their enantiomers and diastereoisomers, their salts are new. 2-Aryl quinoline derivatives (I), their enantiomers and diastereoisomers, their salts are new. A = H, 1-3C alkoxy, 1-6C hydroxy alkyl, 1-3C alkoxy 1-3C alkyl, thiol, 1-6C alkane sulfonyl, or halogen; B' and D = H, 1-6C alkyl or fluoroalkyl, 1 or 2C perfluoroalkyl, or together they form oxo; R1 = phenyl, naphthyl, or heteroaryl having 4 or 5 C atoms and O, N, or S as heteroatom, the phenyl and naphthyl being optionally substituted by 1-3 substituents selected from halogen, OH, NO2, amino, azido, 1-6C alkyl, hydroxy alkyl, alkyl carbonyl, fluoro alkyl or alkylamino, di(1-6C alkyl) amino, 1 or 2 C perfluoroalkyl, 1-6C alkoxy, phenyl, benzyl, or benzyloxy; R2, R3 = H, halogen, or 1-6C alkyl; R4 = H, OH, or halogen; and R5, R6 = H, 1-6C alkyl or fluoroalkyl, 2-6C alkenyl, 3-6C cycloalkyl or cycloalkenyl, 1 or 2C perfluoroalkyl; or R5+R6 together = a 2-6C alkylene chain or a 3-6C alkenylene chain to form a heterocycle which may be substituted by a 1-4C alkyl group. Independent claims are also included for (1) intermediates of formula (III); and (2) pharmaceutical compositions containing (I) together with one or more excipients.

Description

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2-ARYLQUINOLINE DERIVATIVES, THEIR PREPARATION AND THEIR
The present invention relates to 2arylquinoline derivatives, their preparation and their therapeutic application.

dans laquelle : A représente un atome d'hydrogène, un hydroxy, un groupe Ci~3 alcoxy, hydroxy-Cl-6 alkyle, Ci-3 alcoxy-Ci-3 alkyle, un thiol, Ci-6 alkylsulfanyle ou un halogène ; B et D représentent, indépendamment l'un de l'autre, un atome d' hydrogène, un groupe Ci~6 alkyle, fluoro-Ci-6 alkyle ou perfluoro-Cl-2 alkyle, ou B et D forment ensemble un oxo ; Ri représente un phényle, un naphtyle ou un hétéroaryle comprenant 4 ou 5 atomes de carbone et comme hétéroatome un oxygène, un soufre ou un azote, le phényle, le naphtyle ou l'hétéroaryle pouvant être substitué par un, deux ou trois substituants choisis parmi le groupe constitué par un halogène, un hydroxy, un nitro, un amino, un azido, un groupe CI-6 alkyle, hydroxy-C1-6 alkyle, CI-6 alkyl-carbonyle, Ci-6 alkyl-amino, C1-6 dialkyl-amino, fluoro-Cl-6 alkyle, perfluoro- Ci-2 alkyle, C1-6 alcoxy, un phényle et un benzyle , un benzyloxy ; R2 et R3 représentent, indépendamment l'un de l'autre, un atome d'hydrogène, un halogène, un groupe CI-6 alkyle, R4 représente un atome d'hydrogène, un hydroxy ou un halogène, et The compounds correspond to the general formula (I)

wherein: A represents a hydrogen atom, a hydroxy, a C 1 -C 3 alkoxy, hydroxy-C 1-6 alkyl, C 1-3 alkoxy-C 1-3 alkyl group, a thiol, C 1-6 alkylsulfanyl or a halogen; B and D independently of one another are hydrogen, C 1-6 alkyl, fluoro-C 1-6 alkyl or perfluoro-C 1-4 alkyl, or B and D together form oxo; R 1 represents a phenyl, a naphthyl or a heteroaryl comprising 4 or 5 carbon atoms and, as heteroatom, an oxygen, a sulfur or a nitrogen, the phenyl, the naphthyl or the heteroaryl being able to be substituted by one, two or three substituents chosen from the group consisting of halogen, hydroxy, nitro, amino, azido, CI-6 alkyl, hydroxy-C1-6 alkyl, CI-6 alkyl-carbonyl, C1-6 alkyl-amino, C1-6 dialkylamino, fluoro-C1-6alkyl, perfluoro-C1-2alkyl, C1-6alkoxy, phenyl and benzyl, benzyloxy; R2 and R3 represent, independently of one another, a hydrogen atom, a halogen, a C1-C6 alkyl group, R4 represents a hydrogen atom, a hydroxy or a halogen, and

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 R5 and R6 independently of one another are hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, fluoro-C1-6 alkyl, perfluoro; -C1-2 alkyl or R5 and R6, together form a chain C2-6 alkylene, C3-6 alkenylene to give with the nitrogen to which they are attached a heterocycle such as, for example, a piperidyl, azetidinyl or pyrrolidyl, this heterocycle optionally substituted with a C1-4 alkyl group; and their salts.

The preferred compounds according to the invention are chosen from the following subgroups, in which: A represents a hydroxy, a thiol or a halogen and more particularly a hydroxyl; or B and D represent a hydrogen atom; or R 1 represents a phenyl, a naphthyl or a heteroaryl comprising 4 or 5 carbon atoms and as a heteroatom a sulfur or a nitrogen, the phenyl, the naphthyl or the heteroaryl being able to be substituted by one, two or three substituents chosen from the group consisting of a halogen, a hydroxy, a nitro, an amino, an azido, a C1-3 alkyl, hydroxy-C1-3 alkyl, C1-3 alkylcarbonyl, C1-3 alkylamino, C1-3 dialkyl group; amino, fluoro-C1-6alkyl, perfluoro-C1-2alkyl, C1-3alkoxy, phenyl, benzyl and benzyloxy; R2 and R3 represent, independently of one another, a hydrogen atom, a C1-C6 alkyl group more particularly C1-3 alkyl; or R 5 and R 6 represent, independently of one another, a hydrogen atom, a C 1-6 alkyl group more particularly C 1-3 alkyl, or R 5 and R 6 together form a C2-6 alkylene chain, to give with the nitrogen to which they are attached a heterocycle such as, for example, piperidyl, azetidinyl or pyrrolidyl, more particularly piperidyl, this heterocycle being optionally substituted by a C1-4 alkyl group more particularly a Cl-2 alkyl group.

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A particularly preferred subgroup of compounds of formula (I) is that wherein A, B, D, R 1, R 2, R 3, R 5 and R 6 are as defined above in the preferred compound subgroups and R 4 is as defined above.

In particular, the following subgroup of compounds is particularly preferred: A represents a hydroxy, B and D and R4 represent a hydrogen atom, R1 represents a naphthyl, a thiophene, a pyridine or a phenyl, the phenyl being able to be substituted by one, two or three substituents selected from the group consisting of halogen, hydroxy, nitro, amino, azido, C1-3alkyl, hydroxy-C1-3alkyl, C1-3alkylcarbonyl, C1 3-dialkylamino, perfluoro-C1-2alkyl, C1-3alkoxy, phenyl and benzyloxy, R2 and R3 represent, independently of one another, a hydrogen atom or a C1-3alkyl group; or R5 and R6 represent, independently of each other, a C1-3 alkyl group, or R5 and R6 together with the nitrogen to which they are attached a piperidyl, this piperidyl being optionally substituted a C1-2 group alkyl.

In the present application: - C1-z (or C2-z or C3-z), where z can take the values between 2 and 6, represents a carbon chain which can have from 1 (or 2 or 3) to z carbon atoms the term alkyl, alkenyl or alkoxy represents respectively a linear or branched chain alkyl, alkenyl or alkoxy, the term alkylene or alkenylene represents respectively a divalent alkyl or alkenyl with a linear or branched carbon chain, the term heteroaryl represents a aromatic ring comprising 4 or 5 carbon atoms and a heteroatom, such

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 ring is for example a thiophene, a furan or a pyridine, - Pg represents a protecting group; Examples of protecting groups as well as methods of protection and deprotection are given in Protective groups in Organic Synthesis Greene et al., 2nd Ed. (John Wiley & Sons, Inc., New York), and - halogen represents an iodine atom , bromine, chlorine or fluorine.

The compounds of general formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers.

These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures are part of the invention.

When a compound according to the invention has a stereoisomerism, for example of axial-equatorial or Z-E type, the invention includes all the stereoisomers of these compounds.

The compounds of general formula (I) may be in free base form or addition salts with acids, which are also part of the invention. These salts, according to the present invention, include those with inorganic or organic acids which allow a suitable separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, by Examples are tartaric acid, dibenzoyltartaric acid, mandelic acid or camphorsulfonic acid, and those which form physiologically acceptable salts, such as hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogenphosphate, maleate, pamoate, fumarate, 2-naphthalenesulphonate, paratoluenesulphonate. Even though the pharmaceutically acceptable salts are preferred, the others

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 salts form part of the present invention. These salts may be prepared according to methods known to those skilled in the art, for example, by reaction of the base with the acid in a suitable solvent, such as an alcoholic solution or an organic solvent, and then separation of the medium which contains it by evaporation of the solvent or by filtration.

The compounds of the invention may be prepared by methods illustrated by the following schemes.

The compounds of formula (I), in particular those for which A represents hydroxy, may be prepared according to the process described in scheme 1.

Selon ce procédé, on fait réagir un dérivé quinoléine de formule V, dans laquelle Y représente un groupe nucléofuge tel qu'un halogène ou un groupe hydroxy activé par exemple sous forme de triflate, par couplage palladique de Stille avec un composé de formule VI, dans les conditions définies par Mc Kean, D.R. ; Parinello, G. Renaldo, A.F. ; Stille, J. K., J. Org. Chem., 52,1987, 492 pour donner un dérivé éthényl de formule IV. Le dérivé éthényl de formule IV, ainsi Diagram 1

According to this process, a quinoline derivative of formula V is reacted in which Y represents a nucleofugal group such as a halogen or an activated hydroxy group, for example in triflate form, by palladic coupling of Stille with a compound of formula VI, under the conditions defined by Mc Kean, DR; Parinello, G. Renaldo, AF; Stille, JK, J. Org. Chem., 52, 1987, 492 to give an ethenyl derivative of formula IV. The ethenyl derivative of formula IV,

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 obtained, is reacted with an oxidant such as sodium periodate, osmium tetroxide, or metachloroperbenzoic acid followed by hydrolysis in a basic or acidic medium, according to conventional methods known to those skilled in the art for forming a diol of formula III. It is also possible to use the AD-mix to obtain an asymmetric hydroxylation. The Group B geminated hydroxy group of the compound of formula III is selectively protected by a Pg protecting group, according to methods known to those skilled in the art, for example, by forming a silylated ether, so as to obtain the compound of formula II wherein Pg is a protecting group. The hydroxy group borne by the alpha-carbon of the quinoline of the compound of formula II thus obtained may then optionally be activated, in a manner known to those skilled in the art, so as to obtain a nucleofuge group, such as a mesyl group. , a tosyl or a bromine atom. The compound of formula (I) according to the invention is then prepared from the latter compound by reacting it with an amine NHR5R6. This reaction can be carried out in an aprotic organic solvent such as chloroform, methylene chloride at a temperature between room temperature and the reflux of the solvent in the presence of an excess of amine (from 0.2 to 100 equivalents). excess). The compound is then deprotected according to methods known to those skilled in the art to give the compound of formula (I). The meanings of R 1, R 2, R 3, R 4, R 5, R 6 and B in each of the compounds of formulas II, III, IV, V, VI, and the amine NHR 5 R 6 are those indicated for formula (I).

The compound of formula V and also the compound of formula IV may be prepared according to methods described in PCT / FR99 / 02129 and French application No. 9814389.

Alternatively, it is possible to prepare the compounds of formula V according to the methods described below.

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 Thus, the compounds of formula V can be prepared either by a Skraup or Doebner-Miller reaction, according to reaction scheme 2.

Selon ce procédé et dans les conditions définies par Belser P. (Tetrahedron 1996,Vol 52,N 8, 2937-2944) ou avantageusement dans les conditions définies par Z. Song J. Figure 2

According to this process and under the conditions defined by Belser P. (Tetrahedron 1996, Vol 52, N 8, 2937-2944) or advantageously under the conditions defined by Z. Song J.

(Heterocyclic Chem 1993, 30, 17-21), an aniline of formula VII, where Z is hydroxy or methoxy, and an α, β-unsaturated aldehyde or ketone formula VIII are heated in the presence of an desiccant such as sulfuric acid and an oxidant such as sodium iodide to form a Z-substituted quinoline derivative of formula IX. This compound is then treated with an aryl (or heteroaryl) lithian derivative designated Ri-Li in a solvent such as toluene to give a compound of formula V.

The meanings of R 1, R 2, R 3 and R 4 of the compounds of formula V, VII, VIII and IX are those indicated in formula I.

The compounds of formula V can also be prepared by a Friedlânder condensation reaction in reaction scheme 3.

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Selon ce procédé et dans les conditions définies par R. P. Figure 3

According to this process and under the conditions defined by RP

Thummel et al (J. Org Chem 1993, 588, 1666-1671), an aryl (or heteroaryl) ketone of formula XI is reacted with an acyl-2-aniline of formula X, wherein W represents a halogen such as iodine, bromine or chlorine, or a hydroxy or methoxy group, in a high-boiling solvent, such as toluene, in the presence of alcoholic potash. In the case where W is a hydroxyl or a methoxy, this reaction is followed by the transformation of these groups into a leaving group Y, as defined above, according to methods known to those skilled in the art to give the compounds of formula V The meanings of R 1, R 2, R 3 and R 4 of compounds of formula V, X and XI are those given in formula (I).

On the other hand, the compounds of formula (I), in particular those for which A represents a hydroxyl group, may also be prepared, according to scheme 4, from a quinoline derivative of formula XII, for which Y is such as previously defined, by palladium coupling of Stille or Suzuki (Chem Rev. 1995, 95, 2457-2483) with a compound of formula XIII or XIV. The meanings of R 1, R 2, R 3, R 4, R 5 and R 6 of the compounds of formula XII, XIII or XIV are those indicated for formula I.

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Le composé de formule XII peut être préparé selon le procédé décrit dans le schéma 5. Figure 4

The compound of formula XII may be prepared according to the method described in scheme 5.

According to this process, a quinoline compound of formula XX is oxidized, by methods known to those skilled in the art, into an N-oxide compound of formula XIX which, in the presence of acetic anhydride, and under the conditions defined in the patent of Tzeng, C et al US 5,646,164, rearranges into a 2-acetoxy quinoline compound of formula XVIII. The 8-position hydroxyl group of the latter is converted to a nucleofuge group such as a triflate group, and is then opposed to a compound of formula VI by palladic coupling of Stille under the conditions defined by Mc Kean, D.R., et al. (J. Org Chem., 52, 1987, 492), to provide the ethenyl derivative of formula XVII. The acetoxy group at the 2-position of the latter derivative is then converted to a Y group, representing a nucleofugal group such as a halogen or an activated hydroxy group, for example, to a triflate, to give the ethenyl derivative of formula XVI . The quinoline derivative of formula XII can then be prepared according to the reaction sequence described in scheme 1, from the quinoline of formula XVI thus obtained. The meanings of R 2, R 3, R 4 and B of the compounds of formulas XVI, XVII, XVIII, XIX and XX are those indicated in formula I.

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Les composés de formule (I) selon l'invention, dans laquelle A n'est pas un groupe hydroxy, peuvent être préparés à partir du composé de formule (I) où A est un groupe hydroxy, selon le schéma 6. Figure 5

The compounds of formula (I) according to the invention, in which A is not a hydroxyl group, can be prepared from the compound of formula (I) wherein A is a hydroxy group, according to scheme 6.

According to this scheme, these compounds can be prepared from the compound of formula (I) in which A is a hydroxy group, by activating this group in a manner known to those skilled in the art, so as to obtain a nucleofugal group Y, such as as defined above, then reacting it with a nucleophilic group XV "A". This nucleophilic group corresponding to the corresponding nucleophilic entity of the substituent A. The reaction can be carried out, for example, in a solvent such as tetrahydrofuran and by heating to reflux of this solvent.

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Selon ce schéma également, les composés de formule (I) selon l'invention, pour lesquels A est un atome d'hydrogène, peuvent être préparés par déshydroxylation d'un composé de formule (I) correspondant, où A est un groupe hydroxy. La réaction de déshydroxylation peut être effectuée, de manière connue de l'homme du métier, par exemple par réaction avec du triéthylsilane dans l'acide trifluroacétique en chauffant jusqu'au reflux. Figure 6

According to this scheme also, the compounds of formula (I) according to the invention, for which A is a hydrogen atom, can be prepared by dehydroxylation of a corresponding compound of formula (I), where A is a hydroxyl group. The dehydroxylation reaction can be carried out in a manner known to those skilled in the art, for example by reaction with triethylsilane in trifluoroacetic acid by heating to reflux.

The compounds of formula (I) according to the invention, for which A and D are hydrogen atoms, may also be prepared according to the following reaction scheme 7.

Figure 7

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 According to this process, the compound of formula (I) is prepared by reacting a nucleophilic derivative of formula B-CH2MX for which M represents a metal, X represents a halogen and B has the meaning indicated for formula (I), such as for example an organomagnesium or an organolithium, with an imine derivative of formula XXIII obtained by reaction of a secondary amine of formula NHR5R6, for which the meanings of R5 and R6 are those indicated for formula (I) with the exception of hydrogen atom, with an aldehyde of formula XXII. The reaction can be carried out in an organic solvent, such as toluene or benzene, at reflux, with azeotropic distillation. The meanings of R 1, R 2, R 3, R 4, R 5, R 6 and B of compounds XXII and XIII are those indicated for formula (I).

The starting materials (VI, VII, VIII, X, XI, XIII, XIV, XX, XXII, HNR5R6, B-CH2MX) for syntheses of the compounds of formula (I) are directly available commercially, are known in the art. literature or can be synthesized by conventional methods known to those skilled in the art.

The following examples illustrate the methods and techniques suitable for the preparation of this invention without, however, limiting the scope of the claim. Microanalyses and NMR and IR spectra confirm The following examples are intended to illustrate the present invention.

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(1) 3-Méthoxy-2-aminobenzaldéhyde Dans une solution de 100 ml d'éthanol, 100 ml d'acide acétique et 50 ml d'eau, sont dissous 5 g de 3-méthoxy 2nitrobenzaldéhyde. Après addition de 11,4 g de fer et de 1,4 ml d'acide chlorhydrique concentré, le milieu réactionnel est chauffé au reflux durant 10-15 minutes. Après avoir refroidi le milieu réactionnel, sont additionnés 150 ml d'eau et le mélange réactionnel est extrait par 3 x 200 ml de dichlorométhane. Les phases organiques sont rassemblées, lavées avec 500 ml d'une solution saturée d'hydrogénocarbonate de sodium, séchées sur sulfate de magnésium, filtrées et évaporées sous vide pour fournir 4,7 g de 3-méthoxy-2-aminobenzaldéhyde sous forme d'une huile incolore, utilisée sans purification pour l'étape suivante. Example 1 2-Phenyl-3-methyl-8- (1- (R) - [2 '- (R) methylpiperidino] -2-hydroxyethyl) quinoline hydrochloride (I): R1 = C6H5, R2 = CH3, R3 = R4 = B = D = H, A = OH and NR5R6 =

(1) 3-Methoxy-2-aminobenzaldehyde In a solution of 100 ml of ethanol, 100 ml of acetic acid and 50 ml of water are dissolved 5 g of 3-methoxy-2-nitrobenzaldehyde. After addition of 11.4 g of iron and 1.4 ml of concentrated hydrochloric acid, the reaction medium is refluxed for 10-15 minutes. After having cooled the reaction medium, 150 ml of water are added and the reaction mixture is extracted with 3 × 200 ml of dichloromethane. The organic phases are combined, washed with 500 ml of saturated sodium hydrogencarbonate solution, dried over magnesium sulphate, filtered and evaporated under vacuum to give 4.7 g of 3-methoxy-2-aminobenzaldehyde in the form of a colorless oil, used without purification for the next step.

(Yield: quantitative) (2) 2-Phenyl-3-methyl-8-methoxyquinoline 15.3 g (101 moles) of 3-methoxy-2-aminobenzaldehyde and 14 ml (105 moles) of propiophenone are dissolved in 400 ml of ethanol. 1.4 g (25 mol) of potassium hydroxide are added to the reaction mixture and the latter is brought to 100 ° C. for 8 hours. After cooling the reaction medium, the latter is concentrated under vacuum and added with 200 ml of water. A yellow precipitate forms after a few minutes. The medium is filtered and the yellow precipitate is taken up in a mixture of 300 ml of ethyl ether and 200 ml of a 1N solution of hydrochloric acid. The aqueous phase

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 is extracted with 2 x 100 ml of ethyl ether. After addition of 300 ml of methylene chloride, 100 ml of a 3N sodium hydroxide solution are added to the aqueous phase. The latter is then extracted with 3 x 200 ml of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo.

21.2 g of 2-phenyl-3-methyl-8-methoxyquinoline are obtained in the form of a pale yellow solid - mp = 105 ° C. (Yield: 85%) (3) 2-Phenyl-3-methyl-8 To a solution of 21.2 g (85 mmol) of 2-phenyl-3-methyl-8-methoxyquinoline in 500 ml of methylene chloride are added dropwise to -30 C, 17.6 ml (180 mmol). ) of boron tribromide. The cooling bath is then removed and the reaction medium is stirred for 3 hours until it returns to room temperature. Then, the reaction mixture is poured on ice and the medium is basified with sodium hydrogencarbonate. The latter is then extracted with 3 x 200 ml of methylene chloride. The organic phases are combined, dried over magnesium sulphate, filtered and evaporated under vacuum. The residue is purified by chromatography on silica gel (eluent: 3/7 ethyl acetate / cyclohexane) to give 12.7 g of 2-phenyl-3-methyl-8-hydroxyquinoline in the form of a colorless oil.

(Yield: 64%) (4) 2-Phenyl-3-methyl-8-trifluoromethanesulfonatequinoline To a solution of 12.5 g (53 mmol) of 2-phenyl-3-methyl-8-hydroxyquinoline in 150 ml of pyridine are added, dropwise, at 0 C, 16.9 ml (110 mmol) of trifluoromethanesulfonic anhydride. The reaction mixture is then stirred for 16 hours at room temperature. After

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 evaporation of the pyridine, the residue is taken up in 200 ml of water and 100 ml of ethyl acetate. The aqueous phase is extracted with 2 x 100 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel (eluent: 3/7 ethyl acetate / cyclohexane) to give 17.8 g of 2-phenyl-3-methyl-8-trifluoromethanesulfonatequinoline in the form of a beige solid - mp = 85 C. (Yield: 91%) (5) 2-Phenyl-3-methyl-8-vinylquinoline To a solution of 17.7 g (48 mmol) of 2-phenyl-3-methyl-8-trifluoromethanesulfonatequinoline in 250 ml of dioxane degassed with a stream of nitrogen are added sequentially at room temperature 6.3 g (150 mmol) of lithium chloride, 16.8 ml (57 mmol) of tributylvinyltin, and 1, 6 g (1, 5 mmol) of Pd (PPh 3) 4. The reaction medium is then heated at 110 ° C. for 16 hours. After evaporation of the dioxane, the residue is taken up in 200 ml of water and 200 ml of ethyl acetate. The aqueous phase is extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel (eluent: 3/7 ethyl acetate / cyclohexane) to give 11.3 g of 2-phenyl-3-methyl-8-vinylquinoline in the form of a colorless oil. (Yield: 96%) (6) 2-Phenyl-3-methyl-8- (1- (S), 2-dihydroxyethyl) quinoline A suspension of 52 g of ADmix alpha in a mixture of 200 ml of water distilled and 200 ml of tert-butanol are added, at 0 C, 8.6 g (35 mmol) of 2-phenyl-3-methyl-8-vinylquinoline. The reaction mixture is then stirred vigorously with mechanical stirring for 16 hours.

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 hours at the same temperature. 2 g of Na 2 SO 3 are then added. The reaction mixture is stirred for one hour then is taken up in 200 ml of water and extracted with 3 x 200 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel (eluent: 3/7 ethyl acetate / cyclohexane) to give 6.65 g of 2-phenyl-3-methyl-8- (1- (S), 2-dihydroxyethyl) quinoline in the form of an orange solid - mp = 117 ° C. (yield: 69%) (7) 2-Phenyl-3-methyl-8- (1- (S) -hydroxy-2- [tert-butyldimethylsilyloxy] ethyl) quinoline A solution of 6.5 g (23.2 mmol) of 2-phenyl-3-methyl-8- (1- (S), 2-dihydroxyethyl) quinoline in 200 ml of dimethylformamide is added at room temperature, 3 7 g (24.3 mmol) of tert-butyldimethylsilyl chloride and 3.4 g (50 mmol) of imidazole. The reaction medium is stirred for 16 hours. After addition of 200 ml of distilled water, the reaction mixture is extracted with 3 x 200 ml of ethyl acetate. The organic phases are combined, washed with 300 ml of distilled water, dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel (eluent: ethyl acetate / cyclohexane to give 8.4 g of 2-phenyl-3-methyl-8- (1- (S) -hydroxy-2- [tertbutyldimethylsilyloxy] ethyl) quinoline as a colorless oil (Yield: 85%)

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 (8) 2-Phenyl-3-methyl-8- (1- (S) -methanesulfonate-2- [tert-butyldimethylsilyloxy] ethyl) quinoline To a solution of 7 g (17.8 mmol) of 2-phenyl-3 3-methyl-8- (1- (S) -hydroxy-2- [tert-butyldimethylsilyloxy] ethyl) quinoline in 200 ml of ethyl ether are added sequentially, at 0 ° C., 2 ml (26 mmol) of mesyl chloride and 4 ml (27 mmol) of triethylamine. The solution is quickly cloudy and a white precipitate is formed. After stirring for one hour at room temperature, the reaction medium is treated with 150 ml of distilled water and the aqueous phase is extracted with 3 × 200 ml of ethyl ether.

The organic layers are combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 8.4 g of 2-phenyl-3-methyl-8- (1- (S) -methanesulfonate-2- [tert-butyldimethylsilyloxy] ethyl) quinoline as a colorless oil, used without purification for the next step.

(Yield: quantitative) (9) 2-Phenyl-3-methyl-8- (1- (R) - [2- (R) -methylpiperidino] -2- [tert-butyldimethylsilyloxly] -ethyl) quinoline A solution of 7 g (17.8 mmol) of 2-phenyl-3-methyl-8- (1- (S) -methanesulfonate-2- [tert-butyldimethylsilyloxy] ethyl) quinoline 8.8g (88 mmol) of 2- (R) Methylpiperidine in 50 ml of anhydrous chloroform is brought to 60 ° C. for 6 hours. The reaction mixture is concentrated in vacuo and the obtained residue purified by chromatography on silica gel (eluent dichloromethane / methanol: 9/1) to give 3.8 g of 2-phenyl-3-methyl-8- (1- (R) ) - [2- (R) - methylpiperidino] -2- [tert-butyldimethylsilyloxy] ethyl) quinoline as a colorless oil. (Yield: 45%)

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(10) (+)-2-Phényl-3-méthyl-8-(1-(R)-[2-(R)-méthylpipéridino]- 2-hydroxyéthyl)quinoléine Une solution de 0,5 g (1,05 mmoles) de 2-phényl-3-méthyl-8- (1-(R)-[2-(R)-méthylpipéridino]-2-[tert-butyldiméthyl- silyloxy]-éthyl)quinoléine dans un mélange de 15 ml d'acide acétique, 5 ml de tétrahydrofurane, 5 ml d'eau distillée est chauffée à 70 C durant 40 heures puis versé sur un mélange glacé de 150 ml d'éther éthylique et de 150 ml d'une solution saturée d'hydrogénocarbonate de sodium. L'addition d'hydrogénocarbonate de sodium est poursuivie jusqu'à l'obtention d'un pH d'environ 9. Le mélange est alors extrait par 3 x 200 ml d'éther éthylique. Les phases organiques sont rassemblées, séchées sur sulfate de magnésium, filtrées et évaporées sous vide. Le résidu est purifié par chromatographie sur gel de silice (éluant dichlorométhane/méthanol : 9/1) pour fournir 0,3 g de (+)-2phényl-3-méthyl-8-(1-(R)-[2-(R)-méthyl-pipéridino]-2hydroxyéthyl)quinoléine sous forme d'une cire incolore.

(10) (+) - 2-Phenyl-3-methyl-8- (1- (R) - [2- (R) -methylpiperidino] -2-hydroxyethyl) quinoline A solution of 0.5 g (1.05 g) mmol) of 2-phenyl-3-methyl-8- (1- (R) - [2- (R) -methylpiperidino] -2- [tert-butyldimethylsilyloxy] -ethyl) quinoline in a mixture of 15 ml of Acetic acid, 5 ml of tetrahydrofuran, 5 ml of distilled water is heated at 70 ° C. for 40 hours and then poured into an ice-cold mixture of 150 ml of ethyl ether and 150 ml of saturated sodium hydrogencarbonate solution. . The addition of sodium hydrogencarbonate is continued until a pH of about 9 is obtained. The mixture is then extracted with 3 × 200 ml of ethyl ether. The organic phases are combined, dried over magnesium sulphate, filtered and evaporated under vacuum. The residue is purified by chromatography on silica gel (eluent dichloromethane / methanol: 9/1) to give 0.3 g of (+) - 2phenyl-3-methyl-8- (1- (R) - [2- ( R) -methyl-piperidino] -2-hydroxyethyl) quinoline as a colorless wax.

méthyl-8-(1-(R)-[2-(R)-méthylpipéridino]-2-hydroxyéthyl) quinoléine dans 3 ml de méthanol, on ajoute 8,3 ml d'une solution d'acide chlorhydrique 0,1N. Les solvants sont évaporés et le sel obtenu est dissout dans 10 ml d'eau. La solution est filtrée, gelée par un bain de carboglace dans l'acétone, et lyophilisée pendant une nuit pour fournir 0,33 g de chlorhydrate de (+)-2-phényl-3-méthyl-8-(1-(R)-[2-(R)méthylpipéridino]-2-hydroxyéthyl)quinoléine sous forme d'un solide blanc - PF = 68 C. (Rendement : quantitatif) (Yield: 75%) (11) (+) - 2-Phenyl-3-methyl-8- (1- (R) - [2- (R) -methylpiperidino] -2-hydroxyethyl) quinoline hydrochloride solution 0.3 g (0.832 mmol) of (+) - 2-phenyl-3-

methyl-8- (1- (R) - [2- (R) -methylpiperidino] -2-hydroxyethyl) quinoline in 3 ml of methanol, 8.3 ml of a 0.1N hydrochloric acid solution are added. The solvents are evaporated and the salt obtained is dissolved in 10 ml of water. The solution is filtered, frozen with a dry ice bath in acetone, and lyophilized overnight to provide 0.33 g of (+) - 2-phenyl-3-methyl-8- (1- (R)) hydrochloride. - [2- (R) methylpiperidino] -2-hydroxyethyl) quinoline as a white solid - mp = 68 ° C. (Yield: quantitative)

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 EXAMPLE 2 2-Phenyl-3-methyl-8-trifloromethanesulfonyloxy quinoline, pamoate (1) 3-methyl-8-methoxyquinoline In a 1L tricolor equipped with mechanical stirring, 94 ml of concentrated sulfuric acid are placed in 70 ml of water. The mixture is cooled to 0 ° C. with an ice bath and 45 g (366 mmol) of ortho-anisidine are added dropwise, followed by 0.54 g of sodium iodide. The mixture is then heated with an oil bath at 115 [deg.] C. and 50 ml (604 mmol) of methacrolein are added by means of a slurry at a rate of 25 ml / h. The heating is continued 1 h after the addition. The mixture is cooled to room temperature and then thrown on a mixture of ice and sodium carbonate.

It is carried out by extraction with dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and evaporated under vacuum. The residue is purified by chromatography on silica gel (dichloromethane / methanol eluent: 98/2) to give 18.7 g of 3-methyl-8-methoxyquinoline. (Yield = 29.5%) (2) 2-Phenyl-3-methyl-8-methoxyquinoline In a 1 L tricolor, cooled to 0 ° C. with an ice bath, 84 ml of anhydrous THF and 42 ml of anhydrous THF are added. 2M solution of phenyllithium in hexane. The reaction medium is heated to 65 ° C. and a solution of 12 g (69 mmol) of 3-methyl-8-methoxyquinoline in 50 ml of toluene is added dropwise. The mixture is refluxed for 6 h, cooled to room temperature and 50 ml of ethanol are added dropwise. The mixture is concentrated in vacuo and the residue is purified by chromatography on silica gel (heptane / ethyl acetate eluent: 9/1) to give 5.9 g of 2-phenyl-3-methyl-8-methoxyquinoline. (Yield = 35%).

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(3) 2-Phenyl-3-methyl-8-hydroxyquinoline 4.75 g (19 mmol) of 2-phenyl-3-methyl-8-methoxyquinoline and 111 ml of hydrobromic acid are placed in a 1 L flask. %. The mixture is refluxed for 18 h and cooled to room temperature. Sodium bicarbonate is added to alkalinize the solution and is carried out by extraction with ethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated in vacuo to afford 4.3 g of 2-phenyl-3-methyl-8-hydroxyquinoline as an oil. (Yield 77%) (4) 2-Phenyl-3-methyl-8-trifloromethanesulfonyloxyquinoline To a solution of 4.3 g (18.3 mmol) of 2-phenyl-3-methyl-8-hydroxyquinoline in 50 ml of pyridine is added dropwise, at 0 ° C., 6.4 ml (38 mmol) of trifluoromethanesulfonic anhydride. The reaction mixture is then stirred for 16 hours at room temperature. After evaporation of the pyridine, the residue is taken up in 100 ml of water and 100 ml of ethyl acetate. The aqueous phase is extracted with 2 x 100 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated in vacuo to give 6.6 g of 2-phenyl-3-methyl-8-trifluoromethanesulfonyloxyquinoline in the form of a beige solid - mp = 85 ° C. (Yield: 99 %) Using essentially the same method as that of Example 1, using an amine adequate in step (8), was prepared other compound of formula (I) according to the invention.

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Example 3 2-Phenyl-8- (1-diethylamino-2-hydroxyethyl) quinoline, pamoate (I): R 1 = C 6 H 5, R 2 = R 3 = R 4 = B = D = H, A = OH and R 5 = R 6 = C 2 H 5 ( 1) 8-Hydroxyquinoline N-Oxide In a 1L flask, 59.74 g (411 mmol) of 8-hydroxyquinoline, 350 ml (822 mmol) of dichloromethane, 82.2 ml of 35% hydrogen peroxide and 0 52 g (2.5 mmol) of methylrhenium trioxide (MTO). The reaction mixture is stirred at ambient temperature (25 ° C.) for 24 h and then 80 ml of oxygenated water and 0.32 g of manganese dioxide are successively added. The mixture is stirred for 1 h 30 and then decanted. The aqueous phase is extracted with dichloromethane (2 × 200 ml). The organic phases are combined, dried over sodium sulphate, filtered and concentrated under vacuum to give 64 g of 8-hydroxyquinoline N-oxide in the form of an orange solid - mp = 112 ° C. (Yield 97%) (2) 2-Acetoxy-8-hydroxyquinoline 64 g (397 mmol) of 8-hydroxyquinoline N-oxide, 550 ml of acetic anhydride and 40 ml of acetic acid are placed in a 1L flask. The reaction mixture is refluxed (135 ° C.) for 24 h and then 40 ml of acetic acid are added again and heating is continued for 1 h 30 min. The reaction mixture is allowed to warm to room temperature and 400 ml of toluene are added. A precipitate appears and is filtered. 400 ml of toluene are added again and filtered.

The precipitate is washed with 200 ml of ethyl ether and is dried in a desiccator under vacuum over phosphorus pentoxide to provide 70.5 g of 2-acetoxy-8-hydroxyquinoline in the form of a brown solid - mp = C.

(Yield 88%)

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 (3) 2-Acetoxy-8-trifluoromethanesulfonatequinoline In a 1L flask was placed 36 g (176 mmol) of 2-acetoxy-8-hydroxyquinoline and 300 ml. The reaction mixture is cooled with an ice bath and 62.3 ml (370 mmol) of trifluoromethanesulfonic anhydride are added dropwise and stirring is continued at 0 ° C. for 3 h. The reaction mixture is poured onto a mixture of 200 ml of 3M hydrochloric acid and ice. A brown precipitate appears and is filtered and then washed with 3.times.50 ml of water and is dried in a desiccator under vacuum over phosphorus pentoxide to provide 56.6 g of 2-acetoxy-8-trifluoromethanesulfonatequinoline in the form of a brown solid. C. (Yield 96%) (4) 2-Acetoxy-8-vinylquinoline 33.6 g (100 mmol) of 2-acetoxy-8-trifluoromethanesulphonatequinoline are placed in a 1 L flask containing 300 ml of previously degassed dioxane, 12, 7 g of LiCl (300 mmol), 34.9 g (110 mmol) of tributylvinyltin and 5.8 g of tetrakis (triphenylphosphine) palladium. The mixture is heated at reflux for 4 h and then concentrated in vacuo and hydrolyzed by the addition of 200 ml of water. The aqueous phase is extracted with ethyl acetate (4x200 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatographic column on silica (eluent: cyclohexane / ethyl acetate 95/5) to provide a fraction containing 2-hydroxy-8-vinylquinoline and 18.6 g of 2-acetoxy-8-vinylquinoline in the form of a yellow oil.

(Yield = 87%)

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 (5) 2-Hydroxy-8-vinylquinoline In a 1 L flask was placed 18.6 g (87.3 mmol) of 2-acetoxy-8-vinylquinoline, 290 ml of water and 290 ml of methanol. The reaction mixture is heated at 55 ° C. for 2 h and then the methanol is evaporated under vacuum. Extraction is carried out with ethyl acetate (2 × 200 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum to give 15.0 g of 2-hydroxy-8-vinylquinoline as a yellow solid - mp = 96 ° C. (quantitative yield) (6). 2-Trifluoromethanesulfonyloxy-8-vinylquinoline In a 250 ml flask was placed 7.5 g (43.86 mmol) of 2-hydroxy-8-vinylquinoline, 5.32 ml of pyridine (65.78 mmol) and 100 ml of dichloromethane. The mixture is cooled to 0 ° C. with an ice bath and 11.10 ml (65.78 mmol) of trifluoromethanesulfonic anhydride are added dropwise.

Stirring is continued at 0 ° C. for h and the reaction mixture is hydrolysed by addition of 100 ml of water. Extraction is carried out with dichloromethane (3 × 150 ml).

(7) 2-Trifluorométhanesulfonyloxy-8-(1,2-dihydroxyéthyl) quinoléine A une suspension, refroidie à 0 C par un bain de glace, d'ADmix-adans 300 ml, de tert-butanol et 300 ml d'eau, on ajoute une solution de 2-trifluorométhanesulfonyloxy-8vinylquinoléine dans 37 ml, de tert-butanol et 37 ml d'eau. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography on silica (eluent: heptane / dichloromethane 1/1) to provide 7.2 g of 2-trifluoromethanesulfonyloxy-8-vinylquinoline as a yellow oil. (Yield = 52%)

(7) 2-Trifluoromethanesulfonyloxy-8- (1,2-dihydroxyethyl) quinoline To a suspension, cooled to 0 ° C. with an ice bath, of ADmix-adans 300 ml, tert-butanol and 300 ml of water, a solution of 2-trifluoromethanesulfonyloxy-8-vinylquinoline in 37 ml of tert-butanol and 37 ml of water is added.

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(9) 2-Trifluorométhanesulfonyloxy-8-(1-diéthylamino-2-tert- butyldiméthylsilyloxyéthyl)quinoléine A une solution, refroidie à 0 C par un bain de glace, de 13,8 g (30,53 mmoles) de 2-trifluorométhanesulfonyloxy-8-(l'- hydroxy-2'-tert-butyldiméthylsilyloxyéthyl)quinoléine dans 300 ml d'éther éthylique, on ajoute successivement 13,21 ml de triéthylamine et 7 ml de chlorure d'acide méthanesulfonique. Le mélange est agité 30 min à 0 C puis 10 The reaction mixture is stirred at 0 ° C. for 16 h and then sodium bisulfite is added with 300 ml of water. The mixture is stirred for 1 h at room temperature and extracted with ethyl acetate (3x200 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatographic column on silica (eluent: cyclohexane / ethyl acetate 1/1) to provide 12.0 g of 2-trifluoromethanesulfonyloxy-8- (1,2-dihydroxyethyl) quinoline as a yellow oil. (Yield = 80%) (8) 2- Trifluoromethanesulfonyloxy-8- (1-hydroxy-2-tert-butyldimethylsilyloxyethyl) quinoline A solution of 12 g (35 mmol) of 2-trifluoromethanesulfonyloxy-8- (1,2-dihydroxyethyl) quinoline, 5.33 g (78.3 mmol) of imidazole, 5.63 g of tert-butyldimethylsilane chloride in 280 ml of DMF was stirred at room temperature for 16 h. 800 ml of water are added and extraction is carried out with ethyl acetate (3 × 250 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatographic column on silica (eluent: cyclohexane / ethyl acetate 8/2) to give 13.8 g of 2-trifluoromethanesulfonyloxy-8- (1-hydroxy-2-tert-butyldimethylsilyloxyethyl) quinoline in the form of a yellow oil. (Yield = 91%)

(9) 2-Trifluoromethanesulfonyloxy-8- (1-diethylamino-2-tert-butyldimethylsilyloxyethyl) quinoline To a solution, cooled to 0 ° C. with an ice bath, 13.8 g (30.53 mmol) of 2-trifluoromethanesulfonyloxy (8-hydroxy-2'-tert-butyldimethylsilyloxyethyl) quinoline in 300 ml of ethyl ether is successively added 13.21 ml of triethylamine and 7 ml of methanesulfonic acid chloride. The mixture is stirred for 30 minutes at 0.degree.

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 min at room temperature and is hydrolysed by the addition of 300 ml of water. Extraction is carried out with ethyl acetate (3 × 250 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is dissolved in 200 ml of chloroform and 45 ml of diethylamine and the mixture is refluxed for 16 hours. 200 ml of water are added and extraction is carried out with ethyl acetate (3 × 150 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatographic column on silica (eluent: cyclohexane / ethyl acetate 8/2) to give 14 g of 2-trifluoromethanesulfonyloxy-8- (1-diethylamino-2-tert-butyldimethylsilyloxyethyl) quinoline in the form of yellow oil. (Yield = 90%) (10) 2-Trifluoromethanesulfonyloxy-8- (1-diethylamino-2'-hydroxyethyl) quinoline In a 100 ml flask was placed 0.94 g (1.85 mmol) of 2-trifluoromethanesulfonate. 8- (1-diethylamino-2-tert-butyldimethylsilyloxyethyl) quinoline, 14 ml of acetic acid, 5 ml of THF and 5 ml of water. The mixture is heated at 70 ° C. for 20 hours, brought to room temperature, hydrolysed and brought back to neutrality by the addition of normal sodium hydroxide. Extraction is carried out with ethyl acetate and the organic phases are combined, dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by chromatography column on silica (eluent: dichloromethane / methanol 98/2) to give 0.515 g of 2-trifluoromethanesulfonyloxy-8- (1-diethylamino-2-hydroxyethyl) quinoline as a yellow oil.

(Yield = 71%)

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(11) 2-Phényl-8-(1-diéthylamino-2-hydroxyéthyl)quinoléine Dans un tricol de 20 ml, on place 0,1 g (0,254 mmoles) de 2- trifluorométhanesulfonyloxy-8-(1-diéthylamino-2- hydroxyéthyl)quinoléine, 3 ml de toluène, 62 mg (0,51 mmoles) de d'acide phényle boronique, 53 mg (0,38 mmoles) de carbonate de potassium et 17,6 mg (0,0152 mmoles) de tétrakistriphénylphosphine palladium. Le mélange est chauffé par un bain d'huile à 90 C pendant 2 h et on ajoute 10 ml d'eau. On procède à une extraction par l'acétate d'éthyle et les phases organiques sont rassemblées, séchées sur sulfate de magnésium, filtrées et concentrées sous vide. Le résidu est purifié par colonne chromatographique sur silice (éluant : dichlorométhane/méthanol 95/5) pour fournir 40 mg de 2-phényl-8-(1-diéthylamino-2-hydroxyéthyl)quinoléine sous forme d'une huile incolore. (Rendement = 49%) (12) 2-Phényl-8-(l-diéthylamino-2-hydroxyéthyl)quinoléine, pamoate A une solution de 40 mg (0,11 mmoles) de 2-phényl-8-(1diéthylamino-2-hydroxyéthyl)quinoléine dans 1 ml de DMF on ajoute une solution de 43 mg (0,11 mmoles) d'acide pamoïque dans 1 ml de DMF. La solution est agitée pendant 15 min puis 10 ml d'eau distillée sont ajouté. Le précipité jaune obtenu est filtré, lavé par 5 x 5 ml d'eau distillée puis est séché au dessiccateur sous vide sur anhydride phosphorique pour fournir pour fournir 83 mg de 2-phényl-8-(1-diéthylamino-2- hydroxyéthyl)quinoléine, pamoate sous forme d'un solide jaune - PF = 120 C. (Rendement quantitatif) Exemple 4 En utilisant essentiellement les mêmes procédés que ceux des exemples précédents, on a préparé d'autre composé de formule (I) conforme à l'invention. Ces composés sont ceux du tableau ci-après.

(11) 2-Phenyl-8- (1-diethylamino-2-hydroxyethyl) quinoline In a tricolor of 20 ml, 0.1 g (0.254 mmol) of 2-trifluoromethanesulfonyloxy-8- (1-diethylamino-2- hydroxyethyl) quinoline, 3 ml of toluene, 62 mg (0.51 mmol) of phenylboronic acid, 53 mg (0.38 mmol) of potassium carbonate and 17.6 mg (0.0152 mmol) of tetrakistriphenylphosphine palladium . The mixture is heated with an oil bath at 90 ° C. for 2 hours and 10 ml of water are added. Extraction is carried out with ethyl acetate and the organic phases are combined, dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by chromatographic column on silica (eluent: 95/5 dichloromethane / methanol) to give 40 mg of 2-phenyl-8- (1-diethylamino-2-hydroxyethyl) quinoline as a colorless oil. (Yield = 49%) (12) 2-Phenyl-8- (1-diethylamino-2-hydroxyethyl) quinoline, pamoate To a solution of 40 mg (0.11 mmol) of 2-phenyl-8- (1-diethylamino) -hydroxyethyl) quinoline in 1 ml of DMF is added a solution of 43 mg (0.11 mmol) of pamoic acid in 1 ml of DMF. The solution is stirred for 15 minutes and then 10 ml of distilled water are added. The yellow precipitate obtained is filtered off, washed with 5 × 5 ml of distilled water and then dried in a desiccator under vacuum over phosphorus pentoxide to provide 83 mg of 2-phenyl-8- (1-diethylamino-2-hydroxyethyl) quinoline. pamoate as a yellow solid - mp = 120 ° C. (quantitative yield) Example 4 Using essentially the same methods as those of the preceding examples, there was prepared another compound of formula (I) according to the invention . These compounds are those of the table below.

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Board

<Tb>
## EQU1 ##
<tb> 1 <SEP> Ph <SEP> Me <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP> Oil
<tb> 2 <SEP> Ph <SEP> Me <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP>> 215
<tb> 2 <SEP> Ph <SEP> Me <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP>> 215
<tb> 3 <SEP> R <SEP> Ph <SEP> Me <SEP> H <SEP> H <SEP> -CH ((R) Me) - <SEP> OH <SEP> H <SEP> - <SEP > Wax
<tb> (CH2) 4
<tb> 4 <SEP> R <SEP> Ph <SEP> Me <SEP> H <SEP> H <SEP> -CH <SEP> ((R) Me) - <SEP> OH <SEP> H <SEP> HCl <SEP> 68 <SEP>
<tb> (CH2) 4
<tb> 5 <SEP> S <SEP> Ph <SEP> Me <SEP> H <SEP> H <SEP> -CH ((S) Me) - <SEP> OH <SEP> H <SEP> - <SEP > Wax <SEP>
<tb> (CH2) 4
<tb> 6 <SEP> S <SEP> Ph <SEP> Me <SEP> H <SEP> H <SEP> -CH ((S) Me) - <SEP> OH <SEP> H <SEP> Pam <SEP > 158 <SEP>
<tb> (CH2)
<tb> 7 <SEP> S <SEP> Ph <SEP> Me <SEP> H <SEP> H <SEP> -CH ((R) Me) - <SEP> OH <SEP> H <SEP> - <SEP > Wax <SEP>
<tb> (CH2) 4
<tb> 8 <SEP> S <SEP> Ph <SEP> Me <SEP> H <SEP> H <SEP> -CH ((R) Me) - <SEP> OH <SEP> H <SEP> Pam <SEP > 164
<tb> (CH2) <SEP> 4
<tb> 9 <SEP> R <SEP> Ph <SEP> Me <SEP> H <SEP> H <SEP> -CH ((S) Me) - <SEP> OH <SEP> H <SEP> - <SEP > Wax
<tb> (CH2) <SEP> 4
<tb> 10 <SEP> R <SEP> Ph <SEP> Me <SEP> H <SEP> H <SEP> -CH ((S) Me) - <SEP> OH <SEP> H <SEP> Pam <SEP > 125
<tb> (CH2)
<tb> 11 <SEP> Ph (3-NO2) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Oil
<tb> 12 <SEP> Ph (3-NO2) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> him
<tb> 13 <SEP> Ph (4-OMe) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP> Oil <September>
<tb> 14 <SEP> Ph (4-OMe) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 110 <September>
<tb> 15 <SEP> Ph (3-OMe) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP> Oil <September>
<tb> 16 <SEP> Ph (3-OMe) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 120-
<tb> 126
<tb> 17 <SEP> Ph <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP> Oil
<tb> 18 <SEP> Ph <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 120 <SEP>
<Tb>

<Desc / Clms Page number 28>

<Tb>
## EQU1 ## >
<tb> 19 <SEP> Ph (2-F) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP> Oil
<tb> 20 <SEP> Ph (2-F) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP>> 250
<tb> 21 <SEP> Ph (3-CF3, <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP> Oil
<tb> 3 '<SEP> -CF3) <SEP> ~~~ <SEP> ~~~~~~~~
<tb> 22 <SEP> Ph (3-CF3- <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 130-
<tb>3'-CF3)<SEP> 144
<tb> 23 <SEP> Ph (3-Cl, <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb>3'-Cl)
<tb> 24 <SEP> Ph (L3-Cl- <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 120-
<tb>3'-Cl)<SEP> ~~~ <SEP> 130
<tb> 25 <SEP> Ph <SEP> (4-CF3) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb> 2 <SEP> 6 <SEP> Ph (4-CF3) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 129-
<tb> 144
<tb> 27 <SEP> Ph (3-CF3) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP> Oil
<tb> 28 <SEP> Ph <SEP> (3-CF3) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP > 150-
<tb> 160
<tb> 29 <SEP> Ph <SEP> (2-CF3) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP > Oil
<tb> 30 <SEP> Ph <SEP> (2-CF3) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP > 135-
<tb> 140
<tb> 31 <SEP> Ph <SEP> (3-NMe2) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP > Oil
<tb> 32 <SEP> Ph (3-NMe2) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 135-
<tb> 140
<tb> 33 <SEP> Ph (3-NH2) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP> Oil
<tb> 34 <SEP> Ph (3-NH2) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 180
<tb> 35 <SEP> Ph (2-OMe) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP> Oil
<tb> 36 <SEP> Ph (2-OMe) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 115
<tb> 37 <SEP> Ph <SEP> (4-F) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb> 38 <SEP> Ph (4F) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 120-
<tb> 128
<tb> 39 <SEP> Ph (3-F) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP> Oil
<Tb>

<Desc / Clms Page number 29>

<Tb>
<tb> N <SEP> Ri <SEP> R2 <SEP> R3 <SEP> R4 <SEP> R5 <SEP> R6 <SEP> A <SEP> B <SEP> Sel <SEP> F <SEP> C
<tb> 40 <SEP> Ph (3-F) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 120-
<tb> 128
<tb> 41 <SEP> Ph <SEP> (3-F, 3'- <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP > Oil
<tb> F)
<tb> 42 <SEP> Ph <SEP> (3-F- <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP > 120-
<tb>3'F)<SEP> 125
<tb> 43 <SEP> Ph (4-Me) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb> 44 <SEP> Ph (4-Me) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 120-
<tb> 135
<tb> 45 <SEP> Ph (4-Ph) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP> Oil
<tb> 46 <SEP> Ph (4-Ph) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 135-
<tb> 140
<tb> 47 <SEP> Ph (4-OCH2- <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb> Ph)
<tb> 48 <SEP> Ph (4- <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 130OCH2-Ph) <SEP> 140
<tb> 49 <SEP> 2- <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb> naphthalene
<tb> 50 <SEP> 2- <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 140naphthalene <SEP> 145
<tb> 51 <SEP> Ph <SEP> (2-F, 4- <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP> Oil
<tb> F)
<tb> 52 <SEP> Ph (2-F, <SEP> 4- <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 155
<tb> F)
<tb> 53 <SEP> Ph (3-OMe, <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb>3'-OMe,
<tb> 4-OMe)
<tb> 54 <SEP> Ph (3-OMe, <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 155
<tb>3'-OMe,
<tb> 4-OMe)
<tb> 55 <SEP> 2- <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP> Oil <SEP>
<tb> thiophene
<tb> 56 <SEP> 2- <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 109thiophene <SEP> 130
<Tb>

<Desc / Clms Page number 30>

<Tb>
## EQU1 ##
<tb> 57 <SEP> 4-pyridine <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb> 58 <SEP> 4-pyridine <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 148-
<tb> 157
<tb> 59 <SEP> Ph (2-OH) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP> Oil
<tb> 60 <SEP> Ph (2-OH) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 180-
<tb> 185
<tb> 61 <SEP> Ph (2-Cl) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb> 62 <SEP> Ph (2-Cl) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 115-
<tb> 145
<tb> 63 <SEP> Ph (2-NO2) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb> 64 <SEP> Ph (2-NO2) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 117-
<tb> 145
<tb> 65 <SEP> Ph <SEP> (2-NH2) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb> 66 <SEP> Ph <SEP> (2-NH2) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP > 110-
<tb> 130
<tb> 67 <SEP> Ph (2- <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb> C <SEP> (0) <SEP> CH3) <SEP>
<tb> 68 <SEP> Ph (2-C (0) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 115-
<tb> -CH3) <SEP> 130
<tb> 69 <SEP> Ph (2-C (OH) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb> (CH3) <SEP> 2) <SEP>
<tb> 70 <SEP> Ph (2-C (OH) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 120-
<tb> (CH3) 2) <SEP> 140
<tb> 71 <SEP> Ph (2-F) <SEP> Me <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb> 72 <SEP> Ph (2-F) <SEP> Me <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 120-
<tb> 145
<tb> 73 <SEP> Ph (3-CF3) <SEP> Me <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb> 74 <SEP> Ph (3-CF3) <SEP> Me <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 160-
<tb> 170
<tb> 75 <SEP> Ph (2-Cl) <SEP> Me <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb> 76 <SEP> Ph (2-Cl) <SEP> Me <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> Pam <SEP> 130-
<tb> 140
<tb> 77 <SEP> Ph (4-N3) <SEP> H <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H- <SEP> Oil
<tb> 78 <SEP> Ph <SEP> (3-N3) <SEP> Me <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP > Oil
<tb> 79 <SEP> Ph (2-N3) <SEP> Me <SEP> H <SEP> H <SEP> And <SEP> And <SEP> OH <SEP> H <SEP> - <SEP> Oil <September>
<Tb>

<Desc / Clms Page number 31>

 In this Table: - Pam represents a pamoic acid salt, - HCl represents a hydrochloride, - "-" represents a compound in free form, - Et represents an ethyl group, - Me represents a methyl group.

 Moreover, the compounds whose number is accompanied by an R, are in chiral form and R stereochemistry for benzyl carbon carrying the amine. Compounds whose number is accompanied by an S, are in chiral form and stereochemistry S for benzyl carbon carrying the amine. If the amine, that is to say the NR5R6 group has a center of asymmetry, the absolute stereochemistry is specified in the table. All other compounds in the table are racemic.

The compounds of the invention have been subjected to biological tests intended to demonstrate their contractile activity on the urethral and arterial smooth muscles.

1. The in vitro activity of the compounds of the invention has been studied on the urethral and arterial smooth muscles. These tests were carried out on New Zealand female rabbits weighing from 3 to 3.5 kg. The animals were killed by vertebral dislocation, then rings of mesenteric artery and ureter tissue were removed. These rings of tissue were immersed in a modified Krebs solution, oxygenated with a mixture of 95% O 2 and 5% CO 2. Each tissue sample was tensioned at 1 g and then phenylephrine was added at cumulative doses and the dose / response curve was established. After rinsing the samples, the test compound was introduced at cumulative doses and the dose / response curve was established. The contractile effect of each compound is evaluated by the calculation of the pD2 (negative logarithm of the agonist concentration which induces 50% of the maximal contraction) as well as by the effect

<Desc / Clms Page number 32>

 maximum representing the percentage of the maximum contraction obtained with phenylephrine (% Emax).

The results obtained show that the compounds in accordance with the invention have: a pD2 urethra, usually between 4 and 8, a pD2 artery usually less than 3, an Emax urethra greater than 30, usually between 40 and 90; , * a% Emax artery usually less than 5.

2. The in vitro activity of the compounds of the invention has been studied on the saphenous veins of micro-pig Yucatan. The tissue is cut into a helix and is mounted in an organ chamber in a modified oxygen-modified Krebs solution with a mixture of 95% O2 and 5% CO2 kept at 37 C. The vessel is connected to an isometric sensor under a basal tension. of 1 g and is connected to a polygraph allowing the recording of the tension variations. The viability of each preparation is tested by pre-stimulation with 3mM noradrenaline. After rinsing, the compound to be studied is introduced and its concentration-response curve constructed cumulatively until a maximum response is obtained.

The contractile effect of each compound is evaluated by calculating the EC50 (concentration producing 50% of the maximum response).

The compounds of the invention made it possible to obtain a venoconstructive activity with an EC50 value usually of between 1 μM and 100 μM.

<Desc / Clms Page number 33>

The compounds of the invention can be used in the treatment of venous insufficiency and venous ulcer.

3. The in vivo activity of the compounds of the invention on blood pressure and urethral was studied in amyelated rat and rabbit, according to the following protocols: * Rats demedulated Wistar rats are anesthetized and demedulated (according to the described technique) by Gillespie, MacLaren A. and Polock D., A method of stimulating different segments of the autonomic outflow from the spinal column to various organs in the pithed cat and rat; Br. J. Pharmacol., 1970, 40: 257-267) .

The catheters are introduced through the femoral artery and jugular vein. Another catheter is introduced into the urethra by an incision performed in the bladder. The compounds to be tested are administered at increasing doses by intravenous infusion.

The results are expressed in doses (pg / kg) necessary to increase the urethral pressure of 10 cm of water (PUi) or the blood pressure of 10 mmHg (PAi) or 50 mmHg (PA50) - The compounds of the invention thus tested, have made it possible to obtain: a PU10 with doses of less than 500 μg / kg, usually between 5 and 200 μg / kg, a PA10 with doses greater than 600 μg / kg, usually between 600 and 2000 ug / kg, - the PA50 could not be reached.

<Desc / Clms Page number 34>

Rabbits The experiments are carried out on New Zealand female rabbits weighing between 3 and 4 kg, anesthetized with a mixture of Ketamine and Xylazine. The catheters are introduced for the descending aorta into the femoral artery, into a jugular vein and into the urethra (1.5 cm below the bladder neck).

The compounds to be tested are administered 5 to 15 days after the operation, by intravenous administration (i v.) In 5 minutes, and in a single dose (of 10 or 100 μg / kg).

The increase in urethral pressure (PU) and arterial pressure (BP) compared with basal, urethral and arterial pressure was measured here. The results obtained are expressed as a percentage of premedicamentous values at 5 minutes after intravenous (i.v.) administration.

Compounds of the invention thus tested, allowed an increase in PU greater than 50%, usually between 50 and 350% after intravenous administration, and usually between 50 and 200% after gavage. The increase in BP was always less than 10%, usually 0%.

All the above results show that the compounds of the invention have a strong urethral contractile action and a low arterial contractile action.

They can be used as a medicament, particularly as a contracting agent for smooth muscle, and even more particularly, in the treatment of stress urinary incontinence. In this indication, the compounds according to

<Desc / Clms Page number 35>

 The invention has good efficacy and, usually, lesser side effects than the drugs conventionally used for such treatment, especially with regard to the side effects affecting the cardiovascular system, in particular the arterial beds.

The compounds according to the invention can also be used for the treatment of venous insufficiency, migraine, gastrointestinal disorders and as a vasoconstrictor of the nasal mucosa.

The use of the compounds according to the invention for the preparation of medicaments intended to treat the pathologies mentioned above forms an integral part of the invention.

According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound according to the invention.

Thus, these pharmaceutical compositions contain an effective dose of a compound according to the invention or a pharmaceutically acceptable salt, solvate or hydrate thereof, and one or more suitable excipients.

Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active ingredients of formula (I) above. or their salts, solvates or hydrates, may be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, to animals and to humans

<Desc / Clms Page number 36>

 for the prophylaxis or treatment of the disorders or diseases above. Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intranasal, dosage forms. subcutaneous, intramuscular or intravenous administration and forms of rectal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions.

In order to obtain the desired prophylactic or therapeutic effect, the dose of active principle may vary between 0.1 mg and 50 mg per kg of body weight per day. Although these assays are examples of average conditions, there may be special cases where higher or lower dosages are appropriate, such assays also belong to the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the pea and the response of said patient.

Each unit dose may contain from 0.1 to 1000 mg, preferably from 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier. This unit dose may be administered 1 to 5 times per day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.

For example, when preparing a solid composition in tablet form, the main active ingredient is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets may be coated with sucrose, a cellulosic derivative, or other materials.

<Desc / Clms Page number 37>

According to a second example, a preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

The present invention according to another of its aspects, also relates to a method for treating the above pathologies which comprises administering a compound according to the invention.

Claims (6)

 A compound of formula (I) ## STR1 ## wherein: A represents a hydrogen atom, a hydroxy, a C1-3 alkoxy group, a C1-C6 hydroxyalkyl group or a C1-3 group; C1-3 alkoxyalkyl, thiol, C1-6 alkylsulfanyl or halogen; B and D independently of one another are hydrogen, CI-6 alkyl, fluoro-C 1-6 alkyl or perfluoro-C 1- 2 alkyl, or B and D together form oxo; R 1 represents a phenyl, a naphthyl or a heteroaryl comprising 4 or 5 carbon atoms and, as heteroatom, an oxygen, a sulfur or a nitrogen, the phenyl, the naphthyl or the heteroaryl being able to be substituted by one, two or three substituents chosen from the group consisting of halogen, hydroxy, nitro, amino, azido, CI-6 alkyl, hydroxy-C1-6 alkyl, C1-6 alkyl-carbonyl, C1-6 alkylamino, C1-6 dialkylamino, fluoro-C1-6alkyl, perfluoro-C1-2alkyl, C1-6alkoxy, phenyl and benzyl, benzyloxy; R2 and R3 represent, independently of one another, a hydrogen atom, a halogen, a C1-6 alkyl group, R4 represents a hydrogen atom, a hydroxy or a halogen, and R5 and R6 represent, independently of one another, a hydrogen atom, a C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, fluoro-C 1-6 alkyl, perfluoro-C 1-2 alkyl group; or R5 and R6 together form a C2-6 alkylene chain, C3-6 alkenylene to give with the nitrogen to which they are attached a heterocycle, this heterocycle being <Desc / Clms Page number 39>  optionally substituted with a C1-4 alkyl group; and its salts. 2. Compound according to claim 1, characterized in that: A represents a hydroxy, B and D and R4 represent a hydrogen atom, R1 represents a naphthyl, a thiophene, a pyridine or a phenyl, the phenyl being able to be substituted by one, two or three substituents selected from the group consisting of: halogen, hydroxy, nitro, amino, azido, C1-3 alkyl, hydroxy-C1-3 alkyl, C1-3 alkylcarbonyl, C1 3-dialkylamino, perfluoro-C1-2alkyl, C1-3alkoxy, phenyl and benzyloxy, R2 and R3 represent, independently of one another, a hydrogen atom or a C1-3alkyl group; , or R5 and R6 represent, independently of each other, a C1-3 alkyl group, or R5 and R6 together with the nitrogen to which they are attached a piperidyl, this piperidyl being optionally substituted a C1-2 group alkyl. 3. Process for the preparation of a compound of formula (I) according to one of claims 1 to 2, wherein A represents a hydroxy group, characterized in that a compound of formula II is reacted, after a possible activation of the hydroxy group of this compound,

 with an amine NHR5R6, the meanings of R1, R2, R3, R4, R5, R6 and B of the compound of formula II and of said amine being those defined for the compound of formula (I) according to claim 1, the compound thus obtained being subsequently deprotected. <Desc / Clms Page number 40> 4. Medicinal product characterized in that it consists of a compound according to one of claims 1 to 3. 5. Pharmaceutical composition characterized in that it comprises a compound according to one of claims 1 to 3 and one or more suitable excipients. 6. Use of a compound according to one of claims 1 to 3, for the preparation of a medicament for the treatment of urinary incontinence, venous insufficiency, migraine or gastrointestinal disorders.